Tuberculosis (TB) is a significant global health concern and is the second leading cause of death from infectious disease worldwide. Approximately two million deaths are attributed to TB annually. The TB epidemic has continued despite widespread use of the only available licensed TB vaccine, Bacille Calmette-Guerin (BCG), under the World Health Organization (WHO) expanded program on immunization (EPI). Although vaccination with BCG has been successful in preventing certain forms of TB infection in children, BCG has limited efficacy against pulmonary TB infection. Adding to the urgent need for improved TB management, the emergence of TB bacterial strains that are resistant to many of the available TB therapies increases the importance of developing new preventative agents. Mycobacterium tuberculosis, the bacteria that cause TB disease is a NIAID priority pathogen. Emergent BioSolutions Inc., is a biopharmaceutical company headquartered in Rockville, MD with laboratories and manufacturing facilities in the United States and Europe, collectively referred to as Emergent throughout this application. Emergent has formed a joint venture with the University of Oxford to form the Oxford-Emergent Tuberculosis Consortium Limited. (OETC) to rapidly advance the MVA85A tuberculosis vaccine. MVA85A is the world's most clinically advanced next generation vaccine candidate for the prevention of TB and is currently undergoing efficacy testing in a clinical efficacy study in South African infants. The vaccine has been shown to be safe, well tolerated and immunogenic in volunteers evaluated to date. Although MVA85A is clinically advanced, the use of Chicken Embryo Fibroblasts (CEFs) for production of MVA85A is inadequate to meet global demand for MVA85A. We have identified an avian cell line suitable for large-scale commercial manufacture at a reduced cost and are currently developing a manufacturing process for MVA85A. This project will focus on optimizing and characterizing this manufacturing process. Specific Aim 1, process optimization, will improve viral titer and purification yield to increase capacity and lower the cost of goods. Specific Aim 2, process characterization, will define the commercial manufacturing process based on knowledge gained through development and scale-up activities Specific Aim 3, Process Validation and Production of 200L Consistency Lots, will demonstrate that the process is capable of reproducible commercial manufacture and will meet the manufacturing requirements for initial licensure. Specific Aim 4, Process Scale up (200L to 2000L), will increase the process scale from 200L to 2000L to meet global demand for the vaccine. Specific Aim 5, Process Validation and Production of 2000L Consistency Lots, will provide assurance that the commercial manufacturing process performs as expected. In total, these studies will produce a commercial scale manufacturing process that will support the licensure of MVA85A. If licensed, MVA85A would be the first TB vaccine approved for use in over 90 years. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is the second leading killer among infectious diseases globally after HIV and is caused by a NIAID category C priority pathogen. The limited efficacy of the only available licensed TB vaccine, Bacille Calmette-Guerin (BCG), against pulmonary TB and the increase in multi-drug and extensively-drug resistant TB demonstrate the need for improved control measures for TB. The MVA85A TB vaccine has the promise to address this global unmet need to prevent TB disease and hence control the spread of TB.